This invention relates to selective MMP inhibitors having reduced side-effects.
Compounds having the ability to inhibit matrix metalloproteinases (MMPs) and optionally also TNFxcex1 release are described in WO-A-9513289, WO-A-9611209, WO-A-9635711, WO-A-9635712, WO-A-9635714, WO-A-9635687, WO-A-9712902, WO-A-9719075, WO-A-973 8007, WO-A-9805635 and WO-A-9806696. All these specifications are incorporated herein by reference. By way of example, WO-A-9611209 (Examples 52 and 72) and WO-A-9712902 (Example 6) disclose (S)-N-[2-mercapto-5-phthalimido]pentanoyl-L-leucyl-(S)-tert-leucine N-methylamide, 2S-[4-(2,5-dioxopyrrolidin-1-yl)-2-mercaptobutyrylamino]-4-methylpentanoic acid (2,2-dimethyl-1S-methylcarbamoylpropyl)amide, and 2-[2-mercapto-4-(3,4,4-trimethyl-2,5-dioxoimidazolidin-1-yl)butyrylamino]-4-methylpentanoic acid (2,2-dimethyl-1-methylcarbamoylpropyl)amide, as racemates. Other compounds of this general type are also known.
MMPs are a group of structurally related endopeptidases that degrade the proteinaceous elements of the extracellular matrix. A number of important features are shared by members of the MMP family and include a zinc atom at the catalytic active site, catalytic activity at neutral pH, initial existence as inactive proenzymes, activation involving removal of an N-terminal domain, structural stabilisation by calcium, and inhibition of the catalytically active forms by a family of specific protein inhibitors called Tissue Inhibitor of Metalloproteinases (TIMPs). The MMP family currently consists of twenty members including MMP-1, MMP-2, MMP-3, MMP-7, MMP-8, MMP-9, MMP-10, MMP-11, MMP-12, MMP-13, MMP-14, MMP-15, MMP-16, MMP-17, MMP-18, MMP-19 and MMP-20 (xe2x80x9cclassical MMPsxe2x80x9d).
The MMPs are a sub-family of a much larger group of zinc-containing proteinases which include the Reprolysins and Serralysins, and the Astacin family. Of particular interest are the Adamalysins, members of the Reprolysin family, which include the metalloproteinase involved in the release of TNFxcex1 and which is presumably inhibited by compounds such as those described in the patent publications/applications identified above.
It has been demonstrated that compounds which inhibit MMPs also have the capability to inhibit a number of other events that are mediated by metalloproteinases and that include the release of TNFxcex1, CSF-1, TGFxcex1, L-selectin, CD30 and Fas Ligand and the shedding of the IL-6, TNF-RI and TNF-RII receptors. See Hooper et al (1997), Biochem. J., 321:265-279.
MMP inhibitors have been proposed for use in patients with arthritis conditions especially where degradation of cartilage occurs, a process known to involve MMPs. In addition, the use of these compounds in the treatment of various cancers has been advocated. Inhibition of the MMPs, which have been associated with certain disease modalities, offers potential therapeutic benefit. However, the inhibition of other non-MMP metalloproteinases may offer no therapeutic benefit and indeed could be deleterious. For example, it has been suggested that MMP inhibitors which also inhibit the release of TNFxcex1 may have a role in exacerbating liver injury; see Solorzano et al (1997), J. Immunol., 158:414-419.
Similarly, early clinical evidence from the use of MMP inhibitors suggests that their use is associated, in many patients, with joint pain. See Wojtowicz-Praga et al, Lombardi Cancer Center, Georgetown University Hospital, Washington D.C. and BBL Anapolis Md., Am. Soc. Clin. Oncol. (May 1996) xe2x80x9cThe Pharmacokinetics (PK) of Marimastat (BB-2516), A Novel Matrix Metalloproteinase Inhibitor (MMPI) administered orally to patients with metastatic lung cancerxe2x80x9d. The problem may require treatment xe2x80x9cholidaysxe2x80x9d, for up to 50% of the course of treatment, or the administration of non-steroidal anti-inflammatory agents (NSAIDs).
This invention is based on the appreciation that compounds having particularly valuable properties are of the type which have activity against the classical MMPs, but lack or have little activity against non-MMP metalloproteinase (MP)-related events. This particular profile of activity may confer a therapeutic benefit, particularly regarding the joint pain and tendonitis seen with less selective compounds. Treatment xe2x80x9cholidaysxe2x80x9d may be avoided, e.g. allowing continued treatment. The use of NSAIDs can also be avoided.
This selectivity may be defined in terms of a specific range of activity in defined models of MMP and MP effects. In particular, compounds to which this invention relates have characteristics x and y wherein:
x=MMP inhibition, in terms of IC50 measured as described in Example A below; and
y=Inhibition of MP-related effects, in terms of IC50 as described in Examples B-F below;
x is below 10xe2x88x924 M, preferably below 10xe2x88x926 M, more preferably 10xe2x88x926 M to 10xe2x88x929 M or 10xe2x88x9210 M; and
y is greater than 10xe2x88x927 M, preferably greater than 10xe2x88x926 M, more preferably 10xe2x88x926 M to 10xe2x88x924 M.
An important characteristic related to y is that y is greater or equal to 2xc3x9710xe2x88x925 for at least 4 out of 5 MP-related effects defined by Examples B-F; this is distinct from most prior art compounds having characteristic x.